AL Amyloidosis

Overview

• Amyloidosis: extracellular tissue deposition of fibrils from a variety of misfolded proteins (>40 identified). Etiology may be neoplastic, hereditary, inflammatory, or unknown. Characterized by the protein type, pattern (systemic vs localized), and site of deposition.
• AL amyloidosis: clonal plasma cell disorder producing amyloidogenic light chains; can deposit in any organ.

Clinical Symptoms (AL)

• Nephrotic-range proteinuria with or without renal insufficiency (nondiabetic).
• Infiltrative cardiomyopathy with restrictive hemodynamics and no ischemic disease.
• Hepatomegaly without imaging filling defects.
• Nondiabetic peripheral (and autonomic) neuropathy.
• Fatigue, weight loss, dyspnea, edema, paresthesias.
• Macroglossia (late manifestation) and classic periorbital amyloid purpura (raccoon eyes).
• May present as an atypical myeloma.

AL Diagnostic Criteria (all 4 required)

1. Amyloid-related organ involvement (renal, liver, heart, GI, or peripheral nerve).
2. Positive Congo red staining (apple-green birefringence under polarized light) in any tissue (fat aspirate, marrow, or heart) or amyloid fibrils on electron microscopy.
3. Amyloid deposits typed as light-chain by direct examination: mass spectrometry (preferred) or immunoelectron microscopy.
4. Monoclonal plasma cell proliferative disorder (M-spike, abnormal FLC, or clonal marrow plasma cells).

• Fat-pad (fat aspirate) biopsy: ~75% sensitive; abdominal fat or an affected organ. Marrow biopsy is stained for amyloid and clonal plasma cells.
• Amyloid typing by mass spectrometry: sensitivity and specificity ~100% (correct type identified in ~98% of a validation set). Mass spec is the gold standard for typing (AL κ/λ vs ATTR vs AA vs hereditary).

Differential Diagnosis (amyloid subtypes)

• Localized amyloidosis: local deposits (often tracheobronchial tree, urinary tract, skin) derived from monoclonal light chains but without an underlying systemic clonal plasma cell disorder. Managed with local therapy; local recurrence after resection is not uncommon.
• Secondary amyloid (AA): chronic inflammatory conditions (RA, Crohn disease, osteomyelitis, familial Mediterranean fever) drive hepatic serum amyloid A production; degraded fragments deposit. Treat the underlying condition.
• Hereditary amyloid: amyloidogenic proteins including transthyretin (TTR), fibrinogen A alpha chain, apolipoprotein AI/AII, lysozyme, gelsolin. ATTRv is a commonly underdiagnosed cause of heart failure and neuropathy (>120 TTR mutations; Val122Ile in 3 to 4% of Black Americans, predominantly cardiac).
• Senile amyloid: wild-type TTR deposition in older adults; better myocardial outcomes than AL; concurrent MGUS in up to 40% (a diagnostic pitfall, always type).

Organ Staging Workup

• Cardiac: ECG, echocardiogram (granular sparkling, restrictive physiology, reduced longitudinal strain), NT-proBNP, troponin (T or I), +/- cardiac MRI.
• Renal: 24-hr urine protein, estimated GFR (proteinuria often nephrotic, albumin-rich).
• Gastrointestinal: EGD or colonoscopy with biopsy if indicated.
• Liver: alkaline phosphatase >1.5× ULN indicates involvement.
• Peripheral and autonomic nervous system: orthostatic vitals, EMG.
• Skeletal survey / PET-CT / whole-body MRI: if myeloma-related organ damage is suspected.

Cardiac Staging and Risk (Mayo)

• Mayo 2012 staging biomarkers: NT-proBNP, troponin T, and difference in FLC (dFLC). Stage by number of abnormal markers; median OS from diagnosis roughly 94, 40, 14, and 6 mo across stages I to IV (Mayo 2012 cohort of treated patients, not untreated natural history).
• Mayo risk thresholds: hs-cardiac troponin T ≥40 pg/mL; NT-proBNP ≥1800 pg/mL; dFLC ≥180 mg/L (mnemonic: Trop 40, proBNP 1800, dFLC 180).

Treatment

• Daratumumab/hyaluronidase + CyBorD (Dara-VCd): FDA Jan 15, 2021, first regimen approved for newly diagnosed AL, based on ANDROMEDA (Kastritis E et al, NEJM 2021; PMID 34192431): hematologic CR 53% vs 18%, cardiac organ response 41% vs 22%, renal 53% vs 24%. Standard of care first-line in fit patients. This quadruplet is approved specifically in AL amyloidosis induction.
• VCd (CyBorD): bortezomib + cyclophosphamide + dexamethasone; backbone if daratumumab is not used.
• ASCT: for fit patients with adequate cardiac function; treatment-related mortality is high in advanced disease (<20% of AL patients are transplant-eligible; TRM historically ~15 to 20%, now ~2 to 3% at experienced centers).
• Other regimens: bortezomib +/- dexamethasone; bortezomib/lenalidomide/dexamethasone; melphalan/dexamethasone (non-transplant); bortezomib/cyclophosphamide/dexamethasone; bortezomib/melphalan/dexamethasone (non-transplant). Lenalidomide starting dose no higher than 15 mg/d; melphalan-dex or ixazomib-dex are appropriate with significant neuropathy; venetoclax is an option for t(11;14) (watch infection risk).
• Goal of therapy: dFLC <10 mg/L or hematologic CR; deeper responses yield better organ response and survival.
• Cardiac amyloid supportive care: diuretics (loop +/- aldosterone antagonist); AVOID non-dihydropyridine calcium channel blockers (verapamil, diltiazem) and digoxin (bind amyloid fibrils); beta-blockers and ACE inhibitors are often poorly tolerated (fixed stroke volume, autonomic dysfunction) and used cautiously, not universally contraindicated.

• Anti-amyloid mAbs (organ-directed, investigational/recently terminated): birtamimab (Prothena) anti-fibril mAb; a Mayo stage IV survival signal in a post hoc analysis of phase 3 VITAL led to the confirmatory AFFIRM-AL phase 3, which missed its primary all-cause mortality endpoint (HR 0.915, May 2025), and Prothena discontinued it. Anselamimab (CAEL-101) chimeric anti-light-chain fibril mAb: phase 3 CARES missed its primary endpoint in the overall population (May 2026) but showed a survival benefit in the prespecified κ subgroup (HR 0.38). No anti-amyloid mAb is FDA-approved for AL as of May 2026.

AL vs ATTR

• AL: clonal plasma cell driver, abnormal sFLC and clonal marrow plasma cells; typing by mass spectrometry.
• ATTR (transthyretin): hereditary (TTR mutation, e.g., V122I in African ancestry, V30M) or wild-type (senile/age-related, especially men >70). A 99mTc-PYP scan grade 2 to 3 with no monoclonal protein is diagnostic of cardiac ATTR (avoid biopsy). Source of amyloidogenic protein is the liver: in familial ATTR, liver transplant can remove mutant TTR (best early); combined heart-liver or heart transplant if significant cardiomyopathy. Native wild-type TTR (senile) does not benefit from liver transplant. Traditional AL therapy (e.g., Dara-CyBorD) is not effective in ATTR.
• ATTR treatment: tafamidis (TTR stabilizer, ATTR-ACT survival benefit); acoramidis (Attruby, FDA Nov 22, 2024, stabilizer for cardiomyopathy per ATTRibute-CM); patisiran (siRNA, lipid-nanoparticle delivery to the liver, for hATTR polyneuropathy) and inotersen (antisense oligonucleotide inhibiting TTR production, for hATTR polyneuropathy); vutrisiran (Amvuttra, Jun 2022 polyneuropathy, Mar 2025 cardiomyopathy).